Primary immunodeficiency

Question 1

Most common causes of recurrent infections?

Answer 1

Allergies

Immunodeficiencies

Question 2

Incidence of PIs (Primary immunodeficiencies)

Answer 2

1:2000 live births

Question 3

What are PIs

Answer 3

Inherited disorders affecting the functioning of the imnune system, predisposing pt to infection, autoimmune disease, aberrant inflammatory response and malignancy

Question 4

3 main types of PIs

Answer 4

1. Humoral (antibody) deficiency
2. Cellular deficiency
3. Combination humoral + cellular deficiencies

Question 5

Key presenting feature of PIs

Answer 5

Increased susceptibility to infection

Question 6

Specific types of PIs

Answer 6

1. B-cell immunodeficiencies (50%)
2. Combined T-cell and B-cell immunodeficiencies (20%)
3. Phagocyte immunodeficiencies (18%)
4. T-cell immunodeficiencies (10%)
5. Complement immunodeficiencies (2%)

Question 7

Warning signs (1-5/10)
2 or +, further assess

Answer 7

1. 4 or more new ear infections/year
2. 2 or more serious sinus infections/year
3. 2 or more months on antibiotics with little effect
4. 2 or more Pneumonias/year
5. Failure of an infant to gain weight or grow normally

Question 8

Warning signs (6-10/10)
2 or +, further assess

Answer 8

6. Recurrent, deep skin or organ abscesses
7. Persistent thrush in mouth or fungal infection on skin
8. Need for IV antibiotics to clear infections
9. 2 or more deep seated infections, including septicemia
10. Family Hx PIs

Question 9

B cell disorders (common)

Answer 9

1. Selective IgA deficiency: recurrent sinopulmonary infection, GI disorders, Allergy, Cancer, autoimmune disease
2. IgG2 subclass/selective deficiency: same, some Pts: recurrent bacterial infections
3. Transient Hypogammaglobulinemia of infancy: upper or lower respiratory tract infections

Question 10

B cell disorders (uncommon)

Answer 10

1. X-linked agammaglobulinemia (XLA): inf begin at 4-6 mo, pyogenic inf PROMINENT, viral inf possible, susceptibility to encapsulated bacteria, Sinusitis, Otitis Media, Pneumonia
2. Common variable immunodeficiency (CVID): Recurrent upper or lower resp tract inf, Bronchiectasis, Enteropathy, Autoimmune manifestions, Malignancy

Question 11

T cell disorders (common)

Answer 11

DiGeorge anomaly (partial): presents in the first few days of life, dysmorphic facies, Hypocalcemia, Depressed T cell immunity, congenital heart disease

Question 12

T cell disorders (uncommon)

Answer 12

DiGeorge anomaly (complete): thymic aplasia, susc to infection, susc to graft vs host disease (GVHD)

Question 13

Severe combined immunodeficiencies (uncommon)

Answer 13

Severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome, Ataxia Telangiectasia, Chronic granulomatous disease, Leukocyte adhesion deficiency, Complement component disorders

Question 14

Severe combined immunodeficiency (SCID)

Answer 14

FTT, onset of inf neonatal period, opportunistic infections, chronic or recurrent thrush, chronic rash, chronic or recurrent diarrhea, paucity of lymphoid tissue

Question 15

Wiskott-Aldrich syndrome

Answer 15

Eczema, thrombocytopenia, bacterial infection

Question 16

Ataxia Telangiectasia

Answer 16

Vascular malformations, Neurologic defects, Tumors and immunodeficiency

Question 17

Chronic granulomatous disease

Answer 17

Recurrent infections to catalase + organisms (Staph aureus, Aspergillus, Nocardia, Serratia marcescens, E Coli, Burholderia Cepacia)
Granulomas: skin, liver, lungs, lymph nodes

Question 18

Leukocyte adhesion deficiency

Answer 18

Recurrent ST infections
Delayed umbilical cord separation
Severe periodontal disease

Question 19

Complement component disorders

Answer 19

Recurrent pyogenic infection and connective tissue disease

Recurrent infections due to Neisseria sp

Question 20

How do you Dx PI

Answer 20

Using a stepwise approach (4 stages)

Question 21

Stage 1 work up

Answer 21

Hx and PE
CBC + diff
Quantitative Immunoglobulin levels related to age (IgG, IgM, IgA)

Question 22

Stage 2 work up

Answer 22

Specific antibody responses (Tetanus, Diphtheria)
Response to pneumococcal vaccine (before and after) for children 3 y and older
IgG subclass analysis

Question 23

Stage 3 work up

Answer 23

Tetanus and candida skin tests
Lymphocyte surface markers CD3, CD4, CD8, CD19, CD16 , CD56
Mononuclear lymphocyte proliferation studies, using mitogen and antigen stimulation

Question 24

Stage 4 work up

Answer 24

Complement screening: C3, C4, CH50
Enzyme measurements (adenosine deaminase, purine nucleoside phosphorylase)
Phagocyte studies (surface glycoproteins, mobility, phagocytosis)
Natural killer citotoxicity studies
Further complement studies AH50
Neoantigen to test antibody production
Other surface/cytoplasmic production
Cytokine receptor studies
Family/genetic studies

Question 25

CBC and/or quantitative Ig levels abnormal?

Answer 25

Repeat to make sure it was not a lab error, if it remains abnormal (stage 1) further testing indicated (going after stage 1) --> refer to Allergist or Immunologist, they need to evaluate for allergies in addition to immunodeficiencies

Question 26

Why is early Dx of PI critical?

Answer 26

To avoid chronic problems, LT adverse effects and severe morbidity (e.g. Bronchiectasis) Because they can be candidates for bone marrow transplantation (BMT), the younger the better

Question 27

Tx PI

Answer 27

Immunoglobulin therapy: IV (clinic) or SQ (home) | BMT for severe cases

Question 28

SQ Immunoglobulin Tx advantages

Answer 28

Improved QOL, lower cost, lower systemic adverse effects

Question 29

SQ Immunoglobulin Tx disadvantages

Answer 29

More frequent treatments, local reaction at infusion site

Question 30

What are the considerations for transplantation?

Answer 30

Early intervention is preferable before chronic illness and disability sets in For hematopoietic stem cell transp, matched-related donor is better than matched-unrelated (registry) donor For some smaller Pts (<10 kg), cord blood stem cell Tx may be possible You can find study protocols, including gene therapy in www.clinicaltrials.gov

Question 31

IV immunoglobulin therapy, standard protocol

Answer 31

For those with antibody deficiency 400-600 mg/kg infusion q 4 wk Adjust doses and/or interval (poss to q 2-3 wk) depending on clinical response Cons trough (pretreatment) level +300 mg/dl for those starting with a higher serum IgG level Follow clinical response, not just the #s Consider SQ Tx to eliminate trough levels

Question 32

btw... common causes of secondary immunodeficiency?

Answer 32

Viral infections, malignancy, malnutrition, drugs (CS, immunosuppresive therapy, etc)